N-of-1 trial

N-of-1 study (1,2)

• also termed "N-of-1" or "single subject" clinical trials - sometimes referred to as a "single patient trial", receives its name by virtue of its sample size: n is equal to one (2)
  • consider an individual patient as the sole unit of observation in a study investigating the efficacy or side-effect profiles of different interventions
  • ultimate goal of an n-of-1 trial is to determine the optimal or best intervention for an individual patient using objective data-driven criteria
  • n-of-1 trial is a randomised controlled crossover trial in a single patient (2)
  • n-of-1 trial provides a pragmatic approach to individual patient care
    
    
• N-of-1 trials have been pursued routinely in education and learning settings, often in behavioral and psychological assessment settings but, with the exception of studies of pain medications, rarely in medical settings (1)

What is the difference between an N-of-1 trial and a crossover trial? (2)

• in a randomised crossover trial, patients are randomised to one of two interventions and then they receive the other intervention after a washout period
  • i.e. the patient is the unit of randomisation (2)
  • in a randomised crossover trial, participants typically receive only one cycle of treatment, whereas in an n-of-1 trial they receive at least two cycles
• in an n-of-1 trial, the unit of randomisation is the treatment order within a treatment cycle for a patient
  • the n-of-1 trial establishes which treatment is best for a patient
  • in comparison, the traditional crossover trial design estimates which treatment is best for the population
  • generally recommended that an n-of-1 trial includes a minimum of three cycles of treatment to enable the correct decisions about patient care to be made

Despite the dissimilarities between the two study designs, they are both suitable only for studying chronic stable conditions that are not resolved by treatment (2)

Design of N-of-1 trials (1):

• simple crossover designs in which the order of the administration of two compounds, one perhaps being a placebo, is randomized across different subjects enrolled in n-of-1 studies have often been used
  • one treatment or compound is labeled 'A' and the other is labeled 'B'
  • thus, an ABAB design would involve a four-period crossover design
  • number and length of the crossover periods would be dictated by the nature of the outcome and interventions as well as the statistical power associated with the chosen number of observations or data collection points within each period given the likely differential effect of the interventions
  • a greater number of periods within which different interventions are pursued, though more costly and time-consuming, can also help reduce the confounding effects of other lifestyle modifications the patient may pursue - or need to pursue - during the course of the trial in order to treat his/her condition (e.g., dietary modification and exercise regime)
  • duration of time periods with each treatments may not be sufficient for a difference of treatment modalities to become apparent
    • it is possible that for any n-of-1 design, not enough evidence favoring one intervention over another might occur - i.e. the period of time allocated is not sufficient enough for a difference in treatments to become apparent
    • if they both achieve a target but equally well, then either intervention might be appropriate for future use
      • increasing the length or sophistication of the trial may help resolve issues of ambiguity like this
      • is a trade-off, as with any trial design; patient retention is jeopardized with a longer trial
      • important to ensure that the treatment periods are sufficiently long and that statistical methods that appropriately accommodate or consider carryover effects are used to analyze the data
  • use of washout periods between administrations of interventions
    • washout periods can be used to combat carryover effects, but their use may compromise patient safety since they may result in taking a patient off all treatments during the course of the trial (although such an approach is no different in orientation from large trial randomization to a placebo arm, or to the use of washout periods in a population-based trial)
  • randomization to different "treatments"
    • ABAB design raises at least four related design questions. First, should one randomize the sequence in which interventions are administered to a single patient such that they may not be alternating? For example, by randomizing the sequence in a six-period design, the order of the treatments might be AABABB or the possibly more interpretively problematic order AAABBB
      • argument for the use of randomized sequencing, as opposed to simply randomizing the intervention labeled A and B, could be made if the intention was to pursue many n-of-1 trials and then assess the results via combined or meta-analysis where order effects of the treatments might be of interest

Combining and evaluating multiple n-of-1 trials

• if multiple n-of-1 trials investigating the same sets of interventions are initiated, then it is possible to pursue joint or meta-analytic studies of the data generated from those trials
  • such analyses can explore trends in the data that may shed light on the characteristics of patients found to respond to one particular intervention, side-effect profiles, and overt carryover effects and other confounders that could be accommodated in future trials

Considering a study investigating statin treatment and muscle symptoms (3)

• Design
  • series of randomised, placebo controlled n-of-1 trials.
• Participants
  • 200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms
• Interventions
  • participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo
• main outcome measures
  • at the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods
• Results
  • 151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval - 0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins
• Conclusions:
  • no overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins

Notes:

• the practicalities of the treatment protocol meant that participants were allocated with equal probability to one of eight possible sequences, which ensured that all participants received one period of statins and one period of placebo in their first two treatment periods (in random order) and no one was allocated to three sequential periods of the same treatment
• time periods on placebo or atorvastatin
  • it was noted by the authors that "Our two month treatment periods were designed to be long enough to allow the previous treatment to washout, and to allow the current treatment to have an effect. It is possible, however, that this time period was not long enough for some of our patients, and that the scores on the visual analogue scale were affected by treatment from the previous period" (3)
  • another possible inadequacy is whether a two month time period is sufficient for myalgia to occur with statin treatment (4)
    • in a small retrospective study of 45 patients, the mean duration of statin therapy before onset of muscle related symptoms was 6.3 (SD 9.3) months (range 1 week to 4 years) (5)

Reference:

1. Lillie EO et al. The n-of-1 clinical trial: the ultimate strategy for individualizing medicine?Per Med. 2011 Mar; 8(2): 161-173.
2. Sedgwick P. What is an 'n-of-1' trial? BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g2674 (Published 10 April 2014)
3. StatinWISE Trial Group. Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n135 (Published 24 February 2021)
4. Editorial Comment - Jim McMorran; Editor in Chief GPnotebook (March 13th 2021)
5. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy.Arch Intern Med2005;165:2